Advanced glycation end products (AGE) are the result of nonenzymatic glycation and oxidation of proteins. They appear under stress related circumstances including in autoimmune connective tissue diseases, and may form in inflamed tissue due to the oxidation or the myeloperoxidase pathway. AGE have been implicated in a number of diabetes related complications. For example, the characteristic structural changes of diabetic nephropathy, thickened glomerular basement membrane and mesangial expansion, are accompanied by accumulation of AGE, leading to glomerulosclerosis and interstitial fibrosis. Prolonged infusion of nondiabetic rats with AGE has led to the development of similar morphological changes and significant proteinuria. AGE inhibitors such as aminoguanidine have been shown to prevent diabetic nephropathy in diabetic animal models and were recently shown to do the same in one clinical trial on diabetic patients. Also, AGE are a well validated therapeutic target for diabetic retinopathy. Extensive diabetic murine and rat studies have demonstrated the benefit of inhibiting AGE formation in treating this disease.
Atherosclerosis is significantly accelerated in diabetic patients and is associated with greater risk of cardiovascular and cerebrovascular mortality. Animal and human studies have suggested that AGE play a significant role in the formation and progression of atherosclerotic lesions. Increased AGE accumulation in the diabetic vascular tissues has been associated with changes in endothelial cell, macrophage, and smooth muscle cell function.
AGE interact with cell surface receptors on monocytes, macrophages, endothelial cells of the microvasculature, smooth muscle cells, mesengial cells, and neurons. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors. RAGE is made up of three extracellular immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic domain that is involved in signaling. RAGE binds multiple ligands in addition to AGE including S100/calgranulins, amphoterin/HMGB1, and amyloid fibrils. RAGE acts through a signal cascade involving NF-κB. RAGE expression is up-regulated in the presence of RAGE ligands and is elevated in joints of subjects with rheumatoid arthritis (RA).
RAGE has a secreted isoform lacking a transmembrane domain called soluble RAGE (sRAGE). Administration of sRAGE has been shown to restore wound healing (Goova, et al. (2001) Am. J. Pathol. 159, 513-525) and suppress diabetic atherosclerosis (Park, et al. (1998) Nat Med. 4(9): 1025-31). Fusion proteins consisting of a RAGE ligand binding element and an immunoglobulin element are discussed in WO 2004/016229 A2 (Wyeth, Madison, N.J.) and US Patent App. Publication 2006/0057679 A1 (O'Keefe, T. et al.).
There exists a need for novel methods of treatment of AGE-mediated diseases, such as diseases that are associated with an elevated amount of AGE. This need and others are met by the present invention.